DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International Application No. PCT/EP2019/086470, filed 12/19/2019, which claims the priority benefit of EP Application No. 18306783.4, filed 12/20/2018.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/21/2021, 05/18/2023,
09/19/2023, 10/16/2023 and 08/13/2024 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Status of claims
Claims 1 and 23-34 are pending in this application and are currently under examination. New claims 23-34 have been added. Claims 2-22 are cancelled.
Applicant’s arguments, and affidavit filed 03/16/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
Claim 1 of the instant claims is being interpreted by the examiner as a method of treating a patient with cancer by 1.) measuring miR-124 in the patient and 2.) administering the compound of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 25 and 26 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claims 25 and 26 are dependent on claim 1 and drawn to a control sample taken from the patient prior to treatment or prior to the presence of the cancer which is a broader limitation than independent claim 1 in which the patient has been previously selected from a population with cancer. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
This rejection may be overcome by amending the scope of the claims to the patient population established in claim 1.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, and 23-34 are rejected under 35 U.S.C. 103 as being unpatentable over Tazi (WO 2014/111892 A1) in view of Roux (WO 2010/143168 A2).
The instant claims are directed to a method of treating a patient with stomach, gastric, gastrointestinal, colorectal, pancreas, lung, and liver cancer by first measuring miR-124 followed by administering a compound of 8-chloro-N-(4-(trifluoromethoxy)phenyl)quinolin-2-amine.
Tazi et al. teach in an embodiment, a quinoline derivative of the invention may be 8-chloro-N-[ 4-( trifluoromethoxy )pheny1] quinolin-2-amine (Below) wherein the invention concerns a use of at least one miRNA, said at least one miRNA being miR-124, as a biomarker of an activity of a quinoline derivative (pg. 8, lines 1-7). Tazi teaches an unexpected observation that a treatment with quinoline derivatives, such as quinoline derivatives of formula (I) or (II), and in particular with the 8-chloro-N-[ 4-(trifluoromethoxy )phenyl ]quinolin-2-amine, resulted in the removal of the viruses and in a dramatic increase (13-fold relative to control) of miR-124 expression.
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Tazi discloses “The oncoviruses are thus termed because they can be associated with cancers and
malignant infections. There may be mentioned, for example, leukemogenic viruses (such as the
avian leukemia virus (ALV), the murine leukemia virus (MULV), also called Moloney virus, the feline leukemia virus (FELV), human leukemia viruses such as HTLVI and HTLV2, the simian leukemia virus or STLV, the bovine leukemia virus or BLV, the primate type D oncoviruses, the type B oncoviruses which are inducers of mammary tumors, or oncoviruses which cause a rapid cancer (such as the Rous sarcoma virus or RSV).” (pg.. 1, lines 28-34). Tazi also teaches measuring a presence or an expression level of miR-124 in a biological sample previously obtained from said patient, and comparing said presence or expression level to a control reference value, wherein a modulated presence or level of expression of said miRNA relative to said control reference value. As well as a method of assessing an activity of a quinoline derivative by “a- measuring a presence or an expression level of at least one miRNA, said at least
one miRNA being miR-124, in a first biological sample previously obtained from said patient
before administering said quinoline derivative and in a second biological sample previously
obtained from said patient after administering said quinoline derivative; and b- determining if said presence or expression level is modulated in the second biological sample obtained after the treatment as compared to the second biological sample obtained before the treatment; wherein a modulated presence or level of expression of said miRNA is indicative of an activity of said quinoline derivative.” (pgs. 8, line 19- pg. 9, line 5) Tazi also discloses the measured level expression of miR-124 may be at least a two-fold, preferably at least a four-fold, preferably at least a six-fold, preferably at least an eight-fold, and more preferably at least a ten-fold decrease relative to said control reference value (pg. 12, lines 13-15). Tazi also discloses the miR-124 biomarker may be used to monitor or manage quinoline derivatives of formula (I) activity during patient treatment (pg. 13, lines 8-9). Tazi teaches “A method of assessing or monitoring the activity of a quinoline derivative of formula (I) in a patient treated with the quinoline derivative may involve measuring a level of expression of miR-124 in an isolated sample, preferably isolated PBMC (Peripheral Blood Mononuclear Cell), and comparing the measured level of expression to a level of expression of miR-124 in an isolated an isolated sample taken from the patient prior to the treatment. By following the miR-124 level, the activity of the quinoline derivative can be monitored over time (pg. 13, lines 12-17). Tazi also teaches In some embodiments, control samples are taken from the patient prior to treatment or prior to the presence of the disease (such as an archival blood sample). In other embodiments, the control samples are taken from a set of normal, non-diseased members of a population (pg. 16, lines 18-21).
However, Tazi et al. fail to disclose an explicit example of treating a cancer by administering the compound of 8-chloro-N-[4-(trifluoromethoxy )phenyl]quinolin-2-amine.
Roux et al. teach that the invention is in keeping with the evidence as published during the last twenty years of a link between changes in RNA alternative splicing and metastatic invasion which has opened to new therapeutic strategies (pg. 1, lines 25-27). Roux also teaches It has now been found that derivatives of formula (I) as defined in formula (I) hereinafter are able to correct defects of alternative splicing, as illustrated in the experimental data hereinafter, a mechanism closely associated with the invasive progression of metastatic cancers, and on the basis of such activity, the compounds are useful in the treatment of cancer. The present invention therefore relates to compounds of formula (I) as defined below for use as agents for preventing, inhibiting or treating cancer. (pg. 1, line 30-pg. 2, line 4). Tazi discloses a derivative of formula Ib as 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine compound 90 (pg. 43)
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Roux also discloses that colorectal cancer, pancreatic cancer, lung cancer, including non-small cell lung cancer, and liver cancer are cancers which can be treated by compounds of the invention (pg. 77, lines 6-13).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to administer the compound of 8-chloro-N-[4-(trifluoromethoxy)phenyl]quinolin-2-amine to a patient with colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer by using miR-124 as a biomarker to monitor the efficacy of 8-chloro-N-[4-(trifluoromethoxy )phenyl]quinolin-2-amine in treating oncoviruses as taught by Tazi because Roux disclosed 8-chloro-N-[4-(trifluoromethoxy )phenyl] quinolin-2-amine as a treatment for a patient with colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer. See MPEP 2144.05(II)
A person of ordinary skill in the art would have been motivated to treat colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer with a compound of 8-chloro-N-[4-(trifluoromethoxy )phenyl]quinolin-2-amine as disclosed by Roux while monitoring and adjusting treatment based on patients response to treatment using miR-124 as a biomarker to monitor efficacy of 8-chloro-N-[4-(trifluoromethoxy )phenyl]quinolin-2-amine as taught by Tazi and would have given a skilled artisan a reasonable expectation of success in treating cancer.
Response to Arguments
Applicant's arguments filed 03/16/2026 have been fully considered but they are not persuasive.
Applicant argues “selecting a patient suffering from cancer for a treatment by measuring and/or monitoring a presence and/or expression level of miR-124 in the patient” is not taught in Roux and that claim 1 and its dependent claims would not have been rendered obvious by Roux.
The disclosures of Tazi (WO 2014/111892 Al) disclose administering and monitoring efficacy of applicants claimed compound 8-chloro-N-[4-(trifluoromethoxy )phenyl]quinolin-2-amine on oncoviruses associated with cancers as disclosed above and would have been obvious to try on patients with colorectal, pancreatic, lung, including non-small cell lung cancer, and liver cancer while using miR-124 as a biomarker. See MPEP 2144.05(II).
Applicant argues Tazi (WO 2016/009065) does not remotely suggest any efficacy of the disclosed compounds on colon carcinoma itself. Thus, the anticancerous effect of ABX464 on stomach
cancer, gastric cancer, gastrointestinal cancer, colorectal cancer, pancreas cancer, lung cancer, and liver cancer would have been entirely unexpected over the teachings of Tazi, which merely relate to treating inflammation. Consequently, the method of claim 1 would not have been obvious over Tazi.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that while Tazi teaches that miR-124 can be a biomarker for screening
compounds effective in treating inflammatory disease. However, Tazi does not teach or suggest selecting a patient suffering from cancer for a treatment by measuring and/or monitoring a presence and/or expression level of miR-124 in the patient, as recited by claim 1.
It would be obvious to one of ordinary skill that Tazi’s disclosure of miR-124 utility as a diagnostic biomarker for monitoring efficacy of 8-chloro-N-[4-(trifluoromethoxy )phenyl] quinolin-2-amine in viral infections requiring RNA splicing for replication of viruses may also be effective in other conditions in which miR-124 can be measured, specifically in other proliferative diseases such as cancer in which uncontrolled replication of cells occurs.
Conclusion
All claims are rejected, no claims are allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at 571-270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/E.V./Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623